Year : 2004 | Volume
: 15 | Issue : 4 | Page : 489--493
Successful Bone Marrow Transplantation in a Child with X-Linked Hyper-IgM Syndrome
Haddadin Isam, A Al-Wahadneh
Department of Pediatrics, King Hussein medical Center, Amman, Jordan
Consultant Pediatric Oncologist, P.O.Box 926119, Amman 11190
A 13-year-old boy was diagnosed at the age of three years as having hyper IgM Immunodeficiency syndrome (HIgM). It is a rare congenital disease characterized by recurrent infections and very low level of serum immunoglobulin (IgG, IgA) and elevated IgM. Conservative treatment with antibiotics and regular intravenous immunoglobulin (IVIG) was not satisfactory. At the age of five, the patient developed Hodgkin«SQ»s lymphoma, which was treated successfully with chemotherapy. Experience with Bone Marrow Transplantation (BMT) in such cases is limited as a definitive treatment for this kind of syndromes. He was transplanted from his HLA-matched sister, and three years post BMT follow-up he showed good clinical recovery and immunoreconstitution.
|How to cite this article:|
Isam H, Al-Wahadneh A. Successful Bone Marrow Transplantation in a Child with X-Linked Hyper-IgM Syndrome.Saudi J Kidney Dis Transpl 2004;15:489-493
|How to cite this URL:|
Isam H, Al-Wahadneh A. Successful Bone Marrow Transplantation in a Child with X-Linked Hyper-IgM Syndrome. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2020 Sep 22 ];15:489-493
Available from: http://www.sjkdt.org/text.asp?2004/15/4/489/32882
X-linked hyper IgM (XHIM) syndrome is a rare genetic disorder characterized by recurrent infections with opportunistic organisms such as Pneumocystis carinii, Histoplasma capsulatum and cryptosporidium and associated with markedly decreased serum level of immunoglobulins IgG, IgA and IgE, and increased IgM. , In 1993 several researchers demonstrated that this disease is caused by mutations of the CD40 ligand gene located at Xq26. , This functional effect at the mutation is that the CD40 ligand on T-cells cannot interact with the CD40 glycoprotein on the surface of B-cells. This interaction normally mediates Ig synthesis by B-cells. Patients with XHIM syndrome are prone to chronic neutropenia, autoimmune disorders and lymphoma. , In 1995, Thomas et al first reported curative BMT in a child with (HIgM) syndrome from an HLA-matched sister,  and later from matched unrelated donors.  Conventional allogeneic bone marrow transplant (BMT) has been reported to cure (HIgM) syndrome; but it should be performed before the onset of severe liver disease or other organ dysfunction, since conditioning regimens is highly hepatotoxic.  We report a successful allogeneic BMT in a child from his HLA-matched sister. To the best of our knowledge this is the first case performed in Jordan.
A 13-years old boy was diagnosed to have (HIgM) at the age of three years because of recurrent attacks of bilateral ear discharge and chest infection since the age of three months. The diagnosis was made at Jordan University Hospital by Immunoglobulins assay, which showed undetectable level of IgA, IgG and abnormally elevated IgM. Flow cytometry showed normal B, T and NK cells enumeration with normal CD4:CD8 ratio. Activated T cells expression of CD40 and CD40-ligand assay was not performed because it was not available in Jordan. Since the diagnosis, we started the patient on intravenous immunoglobulin (IVIG) 400 mg/kg/ 3 weeks with parenteral antibiotics several times due to repeated admission to hospital with several chest infections in addition to prophylactic oral Trimethoprium-sulfamethoxazole. At the age of five the patient developed stage III Hodgkin's lymphoma (nodular sclerosis) for which he received chemotherapy for six cycles of cyclophosphamide, vincristin, prednisolone and procarbazine (COPP) and the patient had complete remission of the lymphoma. At the age of 10, the patient was referred to King Hussein medical center (KHMC) for allogeneic BMT because of repeated infections. In the transplant unit, the physical examination of head and neck of the patient showed huge bilateral cervical node enlargement with hepatosplenomegaly and enlarged inguinal lymph nodes. His chest and heart were normal.
His investigations confirmed hepatosplenomegaly by ultrasonography with normal complete blood count (CBC), liver function tests (LFTs), kidney function tests (KFT) and chest x-ray. A cervical lymph node biopsy was read as reactive. Flow cytometry phenotypes for primary Immunodeficiency were normal. Cytomegalovirus IgM (CMV-IgM) was positive, while hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) and Epstein-Bar virus IgM (EBV-IgM) were negative. No evidence of bronchiectiasis could be detected. Highresolution chest computerized tomography (CT) scan. Histocompatibility (HLA) A, B and DR were fully matching with the patient's sixteen-year old sister; the test was performed using serology and high resolution poly-chain reaction (PCR). The blood group of the patient and the donor was A positive.
The Bone Marrow Transplant Procedure
A double lumen Hickman line was inserted. The conditioning regimen was started before few days before the operation that included busulfan 4mg/kg/day for four days (total dose 16 mg) (day -9 to day -6), and cyclophosphamide 50 mg/kg/day for 4 days (total dose 200 mg) (day -5 to day -2). We administered intravenous acyclovir, oral fluconazole for CMV and fungal infection prophylaxis, respectively. Ciprofloxacin and heparin were used prophylactically for gut decontamination and veno-occlusive disease (VOD), respectively. Graft versus host disease (GVHD) prophylaxis included the use of cyclosporin at day -1 and methotrexate at day +1, +3, +6. IVIG was given weekly (300 mg/Kg/week during the transplant until engraftment, then every 3 weeks till day + 180 post BMT. Bone marrow was harvested under general anesthesia and a total of 5 x 10 8 /kg of mononuclear cells was infused into the patient, Granulocyte colony stimulating factor (GCSF) was started on day +10, engraftment on day + 13, De-isolation on day + 16. He was discharged from the unit on day + 17 on oral Septrin, acyclovir, fluconazole, cyclosporin and folic acid.
The complications included mild mucositis, which responded to analgesia. One attack of pneumonia on day + 37 responded to Cefatriaxone. Acute GVHD grade II skin and GI at day + 55 was treated with prednisolone and hemorrhagic cystitis at day + 63 (grade II) was treated with I.V. hydration with good response. The patient had no episodes of VOD, chronic GVHD or sepsis.
During the follow-up, the patient had the immunoglobulin level assay every three months post BMT. The serum immunoglobulin concentrations and in vivo antibody response after BMT is shown in [Table 1]. Cyclosporin and IVIG were tapered and stopped at six months post BMT with no recurrent ear or chest infections. Revaccination program was commenced at two years post BMT as the level of immunoglobulin was absolutely within normal limits for the corresponding age. The patient was vaccinated with three doses of inactivated poliomyelitis, diphtheria and tetanus (DT), hepatitis B, influenza, measles mumps and rubella (MMR), and Tuberculosis (BCG). The three years post BMT follow-up showed very happy child and family, normal life activity, with no more recurrent infection and IVIG administration or prophylactic antibiotics.
BMT has been developed as a treatment for several lethal immunodeficencies involving T-cells and phagocytes. BMT was first attempted for SCID and Wiskott-Aldrich syndrome in 1968.  Between 1977-1991 at 13 European centers, 149 patients with 11 different primary Immunodeficiency (PID) were transplanted (HIgM was not among the series) with overall survival of 66 %.  In 1995, Thomas reported the first BMT in a child with (HIgM) syndrome from an HLA-matched sibling. After transplantation, expression of CD40 L on recipient's T cell became equivalent to that on donor's T-lympocytes with full recovery of the immune function.  Since that time, many centers started to report BMT on patients with (HIgM) syndrome, some were transplanted successfully and others died post-BMT due to disseminated infections, GVHD, liver failure and multisystem organ failure. 
Our patient is a 10-year-old boy who did not have liver damage, lung bronchiectasis, neutropenia or any other organ damage. He was conditioned with busulfan/cyclophosphamide in full dose as optimal myeloablative regimen and successful engraftment was achieved at day + 13 post BMT. Since the day of BMT the patient had only one episode of chest infection, which was treated with antibiotics at day + 33 post BMT. The patient was followed up by measuring the level of Immunoglobulins starting from day + 30 post BMT. Before the BMT, the level of IgA and IgG in vitro were not detected, while IgM was elevated compared with normal controls.
After BMT, the production of IgM decreased and that of IgA, IgG increased as seen in the [Table 1]. We noticed that IgM level was first to decline at three months and normalize at 24 months post BMT. The level of IgA started to rise very slowly from 12 months post BMT to normalize at 24 months post BMT.
The expression of CD40 L on activated Tcells lymphocytes was not assessed because it is not available in Jordan. As the patient experienced no recurrent infections and with normalization of immunoglobulin levels post BMT, we considered it a good proof that the patient expressed CD 40 L on T-lymphocytes and immunoglobulin isotype switching from IgM to IgG and IgA was established. Accordingly, we may rely on the serial measurement of immunoglobulin in places where facilities to measure CD 40 L are not available.
At six months post BMT, we tapered and stopped the administration of IVIG and cyclosporin, when the immune reconstitution was started to show some improvement. The patient remained free from recurrent infections until now. Revaccination was commenced at two years post BMT as the levels of immunoglobulins were absolutely within normal limits. The patient was vaccinated with inactivated poliomyelitis, DT, Hepatitis B, pneumovax, influenza, MMR and BCG without any adverse effects.
Allogeneic BMT is better performed before organ dysfunction such as liver disease due to cryptosporidium infections as Khawaja et al described an XHIM patient with severe cryptosporidium infection who died soon after nonmyeloablative BMT. The patient had cryptosporidium ascending cholangitis with portal inflammation, confirmed by liver histology. The cryptosporidium enteritis worsened after BMT and this together with capillary leak syndrome resulted in death. When severe liver failure is associated with HIgM syndrome, orthotropic liver transplantation together with nonmyeloablative BMT could be an option. , Despite the risky procedure due to cryptosporidium infection with gastroenteritis and sclerosing cholangitis, Dimicoli reported complete recovery from the infection after successful BMT in two brothers with HIM syndrome.  Others showed a marked decrease in survival for patients more than 10 years of age; the survival curve showed only 20% of patients was alive at 25 years of age. These data suggest that BMT is a viable therapeutic choice if HLA-matched donor is available. 14,15 In conclusion, based on different experiences and ours, we believe all patients with XHIM syndrome should have allogeneic BMT as soon as possible before they develop multiple organ damage
|1||Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodef Rev 1992;3:101-22.|
|2||Banatvala N, Davies J, Kanariou M, Strobel S, Levinskey R, Morgan G. Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome); a case series review. Arch Dis Child 1994; 71:150-2.|
|3||Korthauer U, Graf D, Mages HW, et al. Defective expression of T-cell CD40 ligand causes X-linked immunodefeciency with hyper-IgM. Nature 1993;361:539-41.|
|4||Di Santo JP, Bonnefoy JY, Gauchat JF, et al. CD40 ligand mutation in X-linked immunodeficiency with hyper IgM. Nature 1993;361:541-3.|
|5||Filipovich AH, Mathur A, Kamat D, Kersey JH, Shapiro RS. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 1994;5:91-112.|
|6||Scholl PR, O'gorman MR, Pachman LM, Haut P, Kletzel M. Correction of neutropenia and hypogammaglobulinemia in X-linked hyper IgM syndrome by allogeneic bone marrow transplantation. Bone Marrow Transplant 1998;22:1215-8.|
|7||Thomas C, de Saint Basile G, Le Deist F, et al. Brief report: correction of X-linked hyper IgM syndrome by allogeneic bone marrow transplantation. New Engl J Med 1995;333: 426-9.|
|8||Amrolia P, Gaspar HB, Hassan A, et al. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. Blood 2000,96:1239-46.|
|9||Hadzic N, Pagliuca A, Rela M, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J of Med 2000;342(5):320-4.|
|10||Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with Wiskott-Aldrich syndrome. Lancet 1968;2:1364-6.|
|11||Fisher A, Landais P, Friedrich W, et al. Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT & the European group for Immunodeficiency. Blood 1994;83:1149-54.|
|12||Khawaja K, Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone-marrow transplantation for CD40 ligand deficiency: a single center experience. Arch Dis Child 2001;84:508-11.|
|13||Dimicoli S, Bensoussan D, Latger-cannard V, et al. Complete recovery from cryptosporidium parvum infection with gastroenteritis and sclerosing cholangitis after successful bone marrow transplantation in two brothers with X-linked hyper IgM syndrome. Bone Marrow Transplant 2003;32:733-7.|
|14||Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper IgM syndrome. J Pediatr 1997;131:47-54.|
|15||Kato T, Tsuge I, Inaba J, Kato K, Matsuyama T, Kojima S. Successful bone marrow transplantation in a child with Xlinked Hyper IgM syndrome. Bone marrow Transplant 1999;23:1081-3.|